K. Blennow

Blood-based immunophenotyping of T cell profiles in patients with neurodegenerative disorders.

BACKGROUND There is increasing evidence for the role of central and peripheral inflammation across neurodegenerative disorders, with animal models and post-mortem studies identifying T-cell infiltration in the brain associated with pathology and neurodegeneration. Peripheral T-cell changes have been measured in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This study examines a unique cohort of blood-based T-cell profiles across a range of neurodegenerative dementias including AD, DLB, FTD, corticobasal syndrome (CBS), PSP, and aged-matched healthy controls. Then it also explores their associations with dementia-relevant plasma biomarkers and clinical outcomes. METHODS Freshly prepared peripheral blood mononuclear cells (PBMCs) from 174 participants (AD = 20, DLB = 24, FTD = 19, CBS = 18, PSP = 58, controls = 35) were studied using a flow-cytometry panel designed to analyse major T-cell subpopulations, including memory and T-helper subtypes. Neurodegeneration-relevant biomarkers (p-tau217, p-tau231, GFAP, NfL, and A-beta42/40) were measured in plasma samples. T-cell populations were compared between groups and in association with biomarkers, and principal components analysis (PCA) was used to identify T-cell profiles and their association with dementia-relevant biomarkers in diagnostic classification and survival prediction. RESULTS There was a significant reduction in the fraction of CD3+ cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17-like cell levels in patients with FTD compared to controls. This increase in Th1/17-like cells correlated with NfL and GFAP plasma levels in patients with FTD. PCA identified five components primarily representing CD4+ memory cell population subsets. After sex and age adjustments, component 4 marked by effector memory types including Th2-like, Th-like1 and Th1/17-like cells was a significant predictor of FTD, however was not as accurate as plasma NfL. Higher scores in specific T-cell components (1 and 3) were associated with reduced mortality across all diseases, with component 3 remaining a significant predictor even when controlling for traditional neurodegenerative biomarkers like NfL and p-tau217. CONCLUSIONS This study provides evidence that T-cell dysregulation is not unified in patients with neurodegenerative diseases. We observe different involvement across different dementia types establishing adaptive immunity as a key contributor to disease heterogeneity. However, although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signature were associated with survival outcomes across diagnostic groups, highlighting their promise for prognostic applications and disease monitoring. The characterisation of T-cell populations across neurodegenerative conditions may inform target development and patient stratification for new interventional trials.

CSF p-tau205: a biomarker of Alzheimer's disease progression and biological staging.

Among soluble tau biomarkers, tau phosphorylation at position T205 (p-tau205) has been suggested to distinctly emergence across Alzheimer's disease (AD) continuum compared to other p-tau and non-phosphorylated tau forms, and a moderate relationship with both amyloid-β and tau aggregated pathologies. To evaluate this and further expand the characterization of this biomarker, we measured cerebrospinal fluid (CSF) p-tau205 using an in-house developed immunoassay in a total of 2069 samples from the BioFINDER-2 (n = 1364) and BioFINDER-1 (n = 705) cohorts. These two cohorts spanned the full AD continuum and were analyzed to assess cross-sectional and longitudinal associations with imaging and clinical measures. CSF p-tau205 levels were elevated in both biologically and clinically advanced disease stages. In Aβ-positive individuals, baseline p-tau205 levels correlated with Aβ-PET (R² = 0.28), tau-PET (medial temporal: R2 = 0.35, neocortical: R² = 0.29), cortical atrophy (R² = 0.15) and cognition (MMSE, R² = 0.15). Baseline p-tau205 predicted subsequent Aβ accumulation (R² = 0.44) and tau-accumulation measured by PET (R² = 0.33). Longitudinal p-tau205 levels increased more steeply longitudinally in Aβ-positive than Aβ-negative participants (β[95%CI] = 0.16[0.12-0.21], p < 0.001). Longitudinal p-tau205 changes were associated with cortical thinning (R² = 0.32) and cognitive decline (R² ≥ 0.41). When incorporating Aβ42/40, p-tau217 and p-tau205 into a conceptual CSF-based staging model, the final p-tau205-positive stage showed the strongest association with cortical atrophy, cognitive impairment, and risk of progression to dementia (HR = 6.40[4.28-9.59]). These findings support CSF p-tau205 as a biomarker of Alzheimer's disease pathology and progression with potential value for biological staging.

Blood-based multimodal biomarker models for differentiating early-onset Alzheimer’s disease from frontotemporal dementia: a longitudinal study of early-onset dementia and family members (LEAF) study

Performance of Alzheimer Disease Plasma Biomarkers in Patients With Prion Diseases

Background and Objectives Prion diseases can mimic Alzheimer disease (AD) at presentation. Alzheimer's Association AD diagnostic criteria suggest that a single abnormal highly specific plasma biomarker (including p-tau217) is sufficient for a biological diagnosis. We investigated the performance of AD plasma biomarkers in distinguishing AD and prion diseases. Methods We examined plasma biomarker data from patients with prion disease from a prospective cohort study recruited through the UK National Prion Clinic. Prion diseases were diagnosed clinically or with autopsy confirmation, and AD was diagnosed clinically with CSF biomarker confirmation. Plasma p-tau217, p-tau181, Aβ42/40 ratio, brain-derived tau (BD-tau), neurofilament light chain (NfL), and glial fibrillary acid protein (GFAP) were measured using Simoa. Median biomarker values in different groups were compared with Kruskal-Wallis test, and area under the receiver operating characteristic curve was used to compare accuracy in distinguishing prion diseases from sporadic AD (sAD). Lumipulse p-tau217 and NfL were measured in a validation study in a different laboratory. Results In the main study, we analyzed 345 samples from 278 individuals (mean age 58 [SD 13.5], 48.2% female), including 204 with prion diseases (121 sporadic Creutzfeldt-Jakob disease [CJD], 11 iatrogenic CJD, 9 variant CJD, 47 slow-progressing inherited prion disease (IPD) and 16 fast-progressing IPD), 33 with AD, and 41 healthy controls. For discriminating prion disease without AD copathology from sAD, none of p-tau217 (area under the curve [AUC] [95% CI] 0.605 [0.486–0.724]), p-tau181 (AUC 0.554 [0.446–0.661]), or GFAP (AUC 0.514 [0.389–0.640]) performed well. Aβ42/40 discriminated moderately (AUC 0.770 [0.684–0.856]). NfL/p-tau217 ratio (AUC 0.996 [0.987–1.000]), NfL (AUC 0.988 [0.974–1.000]), BD-tau/p-tau217 ratio (AUC 0.963 [0.929–0.996]), and BD-tau (AUC 0.934 [0.890–0.978]) discriminated very well. In an independent validation study, consecutive samples were analyzed from 32 patients with sAD and 35 patients with sporadic Creutzfeldt-Jakob disease (mean age 65.0 [SD 6.4], 56.7% female). NfL/p-tau217 again discriminated almost perfectly (AUC 0.986 [95% CI 0.966–1.000]). Discussion Plasma p-tau217 and p-tau181 are increased in both AD and prion diseases (regardless of burden of AD copathology). Diagnosing AD with a single abnormal p-tau plasma biomarker risks misdiagnosing prion diseases as AD. Plasma NfL/p-tau217 discriminates near-perfectly and could act as a flag to suspect prion diseases where this is a diagnostic possibility. Classification of Evidence This study provides Class II evidence that plasma NfL/p-tau217 discriminates patients with CJD from those with AD.